With a 64-month median follow-up, in a preliminary report in abstract form, no differences were observed in event-free survival (89%–92%; P = .38) or OS (91%–96%; P = .98).[Level of evidence: 1iiA]
In summary, these randomized trials support the use of ABVD for four cycles with 20 Gy to 30 Gy IF-XRT. Could the radiation therapy be omitted to minimize late morbidity and mortality from secondary solid tumors and from cardiovascular disease? The NCIC study is the only trial to address this question in patients with early unfavorable HL; although four to six cycles of ABVD alone has improved OS compared with a combined modality approach, the use of EF-XRT in the combined modality arm is excessive by current standards, and late effects will be magnified with these larger fields. In addition, chemotherapy alone was 8% worse in freedom-from-progression compared to the combined modality approach.
How can we balance an improvement in freedom-from-progression using radiation therapy with chemotherapy against late morbidity and mortality from late effects?[16,17] Randomized studies with or without IF-XRT would be required, but no such studies are currently under way. An indirect comparison for using ABVD alone is that the 94% OS seen for early unfavorable patients in the NCIC study  at 11 years is equivalent to the survival seen in the GHSG's HD6 [NCT00002561], HD10 [NCT01399931], and HD11 trials using combined modality therapy at 11 years. A Cochrane meta-analysis of 1,245 patients in five randomized, clinical trials suggested improved survival for combined modality therapy versus chemotherapy alone (HR, 0.40; 95% CI, 0.27–0.61). However, the NCIC study does demonstrate a 92% OS for ABVD alone at a median follow-up of 11.3 years. This would support the use of ABVD for patients with early unfavorable disease. Long-term follow-up, which would account for late toxicities and deaths from combined modality therapy, will not be forthcoming from these trials.
Patients with bulky disease (≥10 cm) or massive mediastinal involvement were excluded from most of the aforementioned trials. Based on historical comparisons to chemotherapy or radiation therapy alone, these patients currently receive combined modality therapy.[20,21][Level of evidence: 3iiiDiii]